Cell death is a final pathway common to a variety of conditions and diseases including neurodegenerative disorders and opthalmological disorders, such as glaucoma, as well as in tissue injury caused by radiation. Although multiple mechanisms effectuate radiation damage, endothelial cell damage may be the primary mode of radiation injury (Fajardo and Berthrong, Pathol. Annu. 1:297 (1998); Reinhold and Buisman, Br. J. Radiol. 46:54 (1973); Reinhold and Buisman, Br. J. Radiol. 48:727 (1975); Paris et al., Science 293:293 (2001); Gaugler, Br. J. Radiol. Suppl. 27:100 (2005). Irradiated brain (Caveness, Natl. Cancer Inst. Monogr. 46:57 (1977)), lung (Ward et al., Radiat. Res. 136:15 (1993)), intestine (Hasleton et al., Histopathology 9:517 (1985)), and kidney (Keane et al., Am. J. Med. 60:127 (1976)) are characterized by decreased numbers or abnormal morphology of endothelial cells. Endothelial cells are by far the most actively dividing cells in neuronal tissue (Noetzel and Rox, Acta Neuropath. 3:326 (1964)), and endothelial cell apoptosis leads to disruption of the blood-brain barrier (Li et al., Cancer Res. 63:5950 (2003)), which is commonly observed in radiation injury (Young et al., Radiology 185:904 (1992)). Electron microscopic observations of irradiated brain demonstrate pinocytotic vesicles, infolded plasma membrane, and intracytoplasmic vacuoles, consistent with increased endothelial cell permeability (Llena et al., Arch. Pathol. Lab. Med. 100:531 (1976)).
Large-scale population radiation exposure to a nuclear device or radiological dispersal device explosion would cause significant mortality and morbidity. Most available treatments of injury resulting from radiation are radioprotective in nature, i.e., treatments effective when administered before or around the time of exposure. However, effective radio-mitigation treatments, i.e., treatments effective when administered after exposure, remain to be elucidated. At present, radiomitigation is limited to off-label use of hematopoietic growth factors, iodide, and Prussian blue. Thus, there is a pressing need in the art for effective post-exposure treatment and, specifically, effective radiomitigants.